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Future Therapies

Science and Technology Bring the Future to the Now

MY Recovery From A severe SCI has been remarkable—I’ve regained far more function than I initially thought possible, and my recovery is ongoing; it continues to this day.

Of course, there are other stories out there like mine that defy what we think we know to be the limits of possibility. What I believe now, based on my experience and research, is that we’ve barely scratched the surface of what there is to learn about the potential for recovery from an acute neurological injury. As I look at the horizon in this field of medicine, I’m convinced we will see remarkable advances over the next ten years.

These promising therapies share a common theme: They take advantage of the intrinsic capacity of neurons that were spared from injury and the connections they make (called “circuits,” because they work like the components of modern electronics) to produce movement and sensation. This phenomenon is the foundation of neuroplasticity, which can be enhanced by “high-intensity therapy” to help these circuits reorganize and stimulate recovery.

There are five areas of research and development where I believe the most important advances will occur:

1. Devices: Robots, exoskeletons, nerve stimulators (epidural electrical stimulation [EES] and transcutaneous electrical stimulation [TCS] of the spinal cord), brain-computer interfaces (BCI), scaffolds for nerve regeneration, and adaptive and recreational devices.

2. Neuroplasticity enhanced by drugs and devices: Devices and drugs to promote neuroplasticity by improving learning, sensory and motor integration, and substitution of one sensory modality for another (like substituting touch—Braille—for vision to read).

3. Regenerative medicine: Stem cell mobilization, differentiation, and transplantation; induced pluripotent stem cells (iPSC); and drugs and scaffolds to promote nerve regeneration.

4. Integrative medicine: Understanding the mechanisms by which complementary therapies such as acupuncture, probiotics, and traditional Chinese medicine work to provide a rich source of new treatments and improved use of these ancient therapies.

5. Clinical trials: An explosion of clinical trials will offer patients the opportunity to test new therapies in a highly regulated environment that involves little or no risk. If the treatment is beneficial, the volunteer might recover important functions such as improved strength and sensation.

Devices

When we look to the future in neurorestoration, my money is on devices. I’m confident that, five years from now, I’ll have dramatically increased my independence because of new devices that are being developed, refined, and tested right now.

Motor devices: Moving an arm or leg requires your brain to send electrical signals to your limb’s muscles, causing them to contract. Neuroscientists call these “move signals.” The part of the brain known as the primary motor cortex helps to calculate the move signals for the limb (Figure 1, see page 10). At the same time, the brain needs to receive signals from the arm or leg telling you where the limb is located relative to the rest of your body and to other objects nearby, as observed by your eyes. This information is then integrated using the sensorimotor cortex and other regions of the brain that monitor balance and touch through a process called sensorimotor integration.

A device that can perform these tasks needs to be highly sophisticated. One way to simplify the process is to take advantage of the nerves that are alive in the arm and leg, as well as in the brain. In theory, these nerves can be reactivated or rerouted to fill the need. There are already several devices capable of performing these tasks and clear paths toward developing even better technologies.

Walking rehabilitation and epidural electric stimulation (EES): One of the most significant disabilities experienced by people with ANI is the inability to walk. If you have a complete SCI above S1, you will have difficulty walking; if you have a TBI or stroke that causes significant damage to the motor or sensory regions of the cortex that innervate the lower limbs, walking will be impaired in proportion to the extent of your injury.

These observations support the theory that these injuries would have no recovery of function, since there’s no connection from the brain to the muscles and nerves below. But in 2011, this belief was shown to be incorrect when a twenty-three-year-old man with complete paraplegia (an SCI from C7 to T1) regained the ability to stand and perform stepping movements voluntarily.¹

Figure 38. EES restoration of walking in SCI

He performed 170 locomotor training sessions over twenty-six months, and then a sixteen-electrode array was placed on the dura (outer covering of the spinal cord that covered the L1 to S1 cord segments) to enable epidural electrical stimulation (EES) of the nerves in that region (Figure 38A, similar to Figure 13; see page 82). The investigators adjusted the stimulation protocol to optimize standing and stepping (Figure 38B). At optimal settings, he was able to stand with minimal assistance and could make stepping-like movements when the settings were optimized for movement. Even more exciting: After seven months, he regained some voluntary control of his legs, although it required EES.

This success with intense rehabilitation and EES therapy shows that the spinal cord is smart; it can use sensory information to produce a coordinated movement without input from the brain. This proves that the spinal cord contains circuits that are not normally used, called central pattern generators (CPGs). CPGs can produce simple movements such as stepping and enable postures like standing.

There have been three major recent advances in the field since 2011:

1. The stimulation protocols have been optimized to allow more sensory signals to activate the spinal cord.² The goal is to reproduce the natural activation of the spinal cord sensory and motor nerves and, in people with incomplete SCI, to send information to the brain.³

2. Patients with SCI were treated within one week of their injury using EES that was delivered to specific nerve bundles in the lumbosacral spinal cord, at a frequency that matched the intended movement. Within one week, this protocol reestablished control of paralyzed muscles during overground walking that improved during rehabilitation. Most impressive, after a few months, the patients regained voluntary control over their paralyzed muscles without stimulation.⁴

3. Transcutaneous spinal cord stimulation was shown to improve the speed and quality of walking for people with chronic (>1 year) incomplete SCI.⁵ This noninvasive therapy in patients with chronic SCI offers potential benefits to thousands of people with SCI. It also suggests that similar approaches could be used to restore upper-limb paralysis and could be used in people with stroke as well.

During these studies, some people also showed improvement in blood pressure, as well as bowel, bladder, and sexual function. Sometimes these improvements were permanent, even after the stimulators were turned off.⁶ These successes point to fantastic possibilities to improve the autonomic and sympathetic nervous systems in all ANIs as we look to the future.

Exoskeletons: The concept for exoskeletons has been around since 1917. Designing and building practical exoskeletons, however, has proved difficult. The first FDA-approved exoskeleton was the ReWalk exoskeleton for everyday use (Figure 29A). The same company, ReWalk Robotics, has also developed an exoskeleton called ReStore for stroke patients, which assists a single leg and synchronizes the gait with the other leg (Figure 29B). Bodyweight-assisted exoskeletons and the ReWalk are beneficial for regaining normal gait, balance, and the strength necessary for safe and efficient walking. Currently, these devices are expensive and can be cumbersome. But the future holds more sophisticated designs, lightweight materials, and better functional capabilities.

Optimization of EES to Obtain Normal Sensorimotor Integration for Walking

To be successful, EES must occur in the correct physical location in the spinal cord and at the correct time during the three phases of a single step (Figure 38B). The figure shows a sixteen-electrode array attached to an electrical pulse generator to stimulate the nerves. Several electrodes are activated to stimulate specific groups of nerves beginning with the swing phase (phase 1), followed by a different set of electrodes activated during weight acceptance (phase 2), and finally, another set activated during propulsion forward (phase 3).⁷ Scientifically, the process is an algorithm for EES stimulation that matches the location and timing of natural motor neuron activation. (An algorithm is a series of mathematical formulas that describe the information necessary to perform a specific movement, such as bending your knee.) Another algorithm that measures real-time foot movements can adjust the location and timing of the stimulation protocols to your current environment.

Neuroprosthetics: Almost everyone with ANI could benefit from specialized neuroprosthetics that incorporate lightweight exoskeleton technology. For example, I would like to kayak again, but I’m unable to do so because of my limited upper-extremity strength. A lightweight neuroprosthesis designed just for my arms that is waterproof, easy to put on, and adjustable to facilitate the motions of paddling would be extremely useful. This would be similar to a balanced forearm orthosis (Figure 34), except that it can strengthen your weak arm and hold on to tools and recreational objects. Developing platforms that contain interchangeable components for specific muscles and joints, which can be easily individualized with 3D printing, would be helpful for anyone with an ANI. Continuous rehab is essential to maximize your recovery. I believe that use of these devices will be a cost-effective means to promote neuroplasticity and functional recovery.

Sensory Devices

We rely on constant input from different types of sensory cells (mechanoreceptors, photoreceptors, chemoreceptors, thermoreceptors) in specialized organs to obtain real-time information about our environment. Signals from sensory organs travel to the spinal cord and then to the sensory areas in the brain, where they are processed and interpreted (except for cranial, olfactory, optic, and trigeminal nerves that are more accurately considered part of the central nervous system). Multiple sensations are frequently integrated to create a perceptual experience. For example, I enjoy good wine. The perceptual experience is a combination of the color of the wine, the smell of the bouquet, the multiple tastes I perceive when I swirl it in my mouth, and the flavor that it generates when combined with food. Many of the things we enjoy most stimulate multiple sensory organs and create unique experiences.

Hearing and speech are the top two disabilities after ANI, because they prevent communication and social interactions, the psychological mainstays of our existence.

Hearing: For people with ANI, especially stroke and TBI, loss of hearing may be so profound that even hearing aids aren’t satisfactory. One option is to use a cochlear implant, which bypasses the lower parts of the brain and acts as a neuroprosthesis to restore hearing.⁸ It replaces the normal hearing process with electric signals that directly stimulate the auditory nerve. If you receive a cochlear implant and intense auditory training, you should be able to interpret these auditory signals as sound and speech.⁹ Future devices to enable hearing will likely be less invasive and deliver even better hearing.

Vision: Loss of vision is primarily a problem for people whose stroke or TBI has damaged the part of the brain that contains the visual cortex (Figure 1, occipital lobe). When this occurs on one side of your brain, you lose vision in the opposite field of view proportionate to the size of the stroke. This blind spot creates a large area that cannot be seen without turning your head, which leads to an increased propensity for falls and accidents when driving. But there’s strong evidence that, after sufficient time and practice, the injured brain can learn to see again. People with blindsight can recover their vision, and we have the ability to respond to images that we don’t consciously see (see Figure 7, page 45). With intense practice, you can learn to be aware of and process these images, using a computerized learning program that is individualized for you. Learning takes a lot of time, so to accelerate learning, there have been trials of both drugs and devices. A 2019 clinical trial showed that a noninvasive electrical current, transcranial random noise stimulation (tRNS), had remarkable effects to speed up recovery of vision.¹⁰ Translation of this technology into clinical practice will likely take several years, but it offers more rapid and greater recovery of sight for people who have damaged their occipital lobe and visual cortex.

Position, motion, and temperature: These three senses are part of the somatosensory system, which also includes perception of touch, pressure, temperature, and vibration. The nerves that comprise the somatosensory system are frequently damaged after an ANI, either in the brain (stroke or TBI) or in the spinal cord (SCI). Several studies have shown that sensation-specific training (e.g., repetitive exposure to liquids of different temperature, movement of fingers and toes) combined with stimulation by transcranial random noise stimulation (tRNS) or transcranial magnetic stimulation (TMS) can significantly improve many kinds of sensation.¹¹ Examples include fine motion of your hands to enable you to button up a shirt, thread a needle, drive a car, type and use a mouse on your computer, and play video games.

Pain: Pain, or nociception, is perceived by the stimulation of sensory nerves. Devices that control pain usually involve spinal cord stimulation (SCS; Figure 13, see page 82). SCS refers here to a basic type of EES in which the 16-electrode array is placed in the thoracolumbar region to block pain from that region. Placement in the cervical region is possible but has more risks because cranial nerves exit from the cervical spinal cord. SCS relieves pain in people with ANI, as well as people with spinal stenosis and arthritis, by masking pain signals with electrical signals that block nerve impulses from nociceptive nerves. These devices are FDA-approved for treatment of chronic pain of the trunk, limbs, and low back, and for complex regional pain syndrome (CRPS). Over the last ten years, new kinds of stimulation have made SCS more effective and safer, including wireless systems, miniaturization, and better electrodes. This area of medicine will continue to improve in efficacy and safety in the future and become less invasive.

Advanced Technology Devices

Brain-computer interfaces (BCI): BCI is the most sophisticated technology to help people with paralysis. It’s still in a highly experimental state and will likely not be commercially available for several years. BCI comprises: 1) electrodes implanted in the brain’s motor cortex, under the skull over the dura, or on the skull itself like an EEG electrode, which detect electrical signals while you think of a desired movement; 2) a computer interface to decode the signals into machine language that enables computers to process the information; 3) transmission of the information to a neuroprosthesis such as a robotic arm or hand, or to an exoskeleton such as the balanced forearm orthosis (Figure 36) and, ultimately, to nerves and/or muscles that respond to the signal; and 4) a sensory device that provides feedback on the resulting movement.

The current state of development has resulted in devices that enable a person with paraplegia to operate a BCI-robotic arm, which controls reach and grasp movements. But these BCI devices require invasive electrodes in which the skull is opened and the electrodes are implanted into the brain tissue, so they aren’t useful for the long term. In 2019, a French study reported the use of a BCI implanted between the skull and the dura (which covers the brain) for twenty-four months. A tetraplegic man used the device to control a virtual avatar, and in the laboratory he controlled a four-limbed exoskeleton to make stepping movements, although he required bodyweight support for balance.¹² This provides the strongest evidence to date that BCI technology can become safe, durable, and functional in everyday life. The development of electrodes that are less invasive, similar to those used for EEGs, will improve the transition of BCI from the laboratory to the community.

Artificial intelligence (AI): AI will become an important tool for neurorehabilitation, because the algorithms that will be developed to decode information from the sensorimotor cortex will be individualized, which should enable more accurate and efficient movement. When multiple algorithms are put together, a complete movement, such as reach and grasp, is obtained. The results from hundreds or even thousands of users will be analyzed by scientists and AI experts to identify key patterns that can be used to optimize routine movements such as opening a door or jar, reaching for and grasping a glass, or grasping and pulling a zipper. Using these standard algorithms, AI will then analyze your unique data to create an algorithm that is specific for you, based on your own muscle strength, flexibility, and range of motion.

Speech synthesis: Speech synthesis is the artificial production of human speech. Fifteen years ago, this would have been a heroic achievement, but today almost 1 billion people worldwide routinely use smart speakers such as Siri (Apple), Alexa (Amazon), and OK Google (Android) to request information and enable dictation. The future will bring us the “Internet of Things,” a network of physical objects—“things”—that are embedded with sensors, software, and other technologies to connect and exchange data with control devices over the Internet. Currently the “smart home” uses devices such as smartphones and smart speakers to control lights, thermostats, and home security systems. For those of us with ANI limitations, this technology will offer almost unlimited accessibility and interaction with our environment. Perhaps the last frontier will be to combine this technology with electrical signal recordings in the brain to enable speech production and speech recognition for stroke and TBI survivors who have sufficient damage to make verbal communication impossible.

Adaptive and Recreational Devices

Sports and recreational activities: After ANI, sporting activities can be difficult, primarily because of the following limitations: 1) decreased range of motion, poor strength, and lack of sensation in the upper extremities, especially the hands; 2) poor balance due to a lack of core strength; and 3) paralysis of the lower limbs requiring the use of wheelchairs for movement. Improving upper-extremity function is the most difficult problem, because the range of motion required for normal function is so great. Currently, there are task-specific adaptive technologies that can assist with simple movements, such as rotating your hand and swinging your arm forward. However, it will require BCI technology to achieve upper-extremity strength and range of motion to participate in sports like tennis or golf. The problems with improving balance and core strength are similar. Neuroprosthetics that are universal in terms of range of motion and strength but adjustable to the demands of a specific sport are the hope of the future. I think it’s also likely that improvements in exoskeleton and epidural electrical stimulation technology will have significant crossover benefits for sports and recreation.

The biggest change recently has been dramatic improvements in wheelchair technology that enable people with ANI to move rapidly in one direction. It’s still difficult to change direction, especially when going backward, and there’s also significant overuse of the shoulder, causing damage to the rotator cuff. Because so many sports and recreational activities require movements that are multidirectional and require the use of both hands, wheelchair movement represents a great opportunity for the use of BCI technology. Specifically, the ability to think of movements that are then carried out by servomotors like those present in exoskeletons will enable an “intuitive” hands-free approach to mobility. This advance will allow you to use both hands for sports. For recreation, the ability to hike, or climb over rough terrain, using a “smart” wheelchair, will be possible using intelligent controls similar to self-driving cars and advances in battery power and weight that improve the distance you can travel.

Transportation: In the future, the widespread use of self-driving vehicles will enable almost everyone with an ANI to “drive.” The only limitation will be getting in and out of vehicles.

Regenerative Medicine

Stem Cell Mobilization, Differentiation, and Transplants

What is a stem cell? There are several kinds of stem cells that all share two properties: self-renewal and differentiation. Self-renewal is the ability of cells to grow without losing the ability to differentiate. Differentiation is the ability of stem cells to change into specialized cells that make up adult tissues, such as neurons, astrocytes, and microglial cells in the brain, which each perform specific functions. Stem cells can be obtained from human embryos or adult tissues by culturing the cells in special growth media. They also can be made in the laboratory by genetically reprogramming a differentiated, specialized cell to become similar to embryonic stem cells. For example, skin cells called fibroblasts are injected with powerful proteins known as transcription factors, which are similar to factors found during embryonic development. Stem cells made by this technique are called induced pluripotent stem cells (iPSCs). Since these cells can be obtained from the person who will be transplanted with them (autologous donation), immune compatibility is greatly increased.

What is nerve regeneration? Nerve regeneration refers to the regrowth or repair of neurons after injury. More broadly, it encompasses the regeneration of nervous tissue, which includes support cells such as glia, astrocytes, and oligodendrocytes. Stem cells provide a unique resource to regenerate nervous tissue because they are similar to the cells present in embryonic development that formed the complex nervous tissue that is the brain and spinal cord. The alternative approach of transplanting mature specialized cells and expecting them to “self-organize” into functional nervous tissue is unlikely to be successful.

Challenges in the clinical use of stem cells for tissue regeneration. The concept of using stem cells to restore dead or damaged nerve cells looks promising, based on animal studies. But six major concerns must be addressed before human tissue-specific stem cell transplants can occur:

1. Incorporation of stem cells into tissues requires an environment that provides the stem cells with information about their correct location and interactions with other cells in the tissue.

2. The timing of stem cell transplants may be important. In people with ANI, there may be a window of only one or two days immediately after the injury for a successful transplant due to inflammation and scar formation.

3. Production of sufficient numbers of stem cells to “fill in” the space left behind may be difficult, especially for iPSCs, which can no longer grow once they differentiate.

4. Making transplanted stem cells differentiate into fully mature tissue. While the cells may appear to be appropriately differentiated, they may not function properly after transplantation.

5. There are significant concerns that the transplanted cells may not remain differentiated. In particular, making iPSCs currently requires the use of tumor-promoting transcription factors that are transferred into cells using viruses. These viruses and factors are known to cause mutations in your DNA and increase cell growth, potentially causing cancer.

6. Consistent stem cell production may be technically difficult, making the success rate low even prior to transplant.

What you should know before being treated with stem cells: The stem cell field is still very new; all legitimate stem cell transplants for people with ANI are currently being given only in clinical trials. These trials, known as phase 1–2 trials, are designed to test safety and proper dose. While it’s possible to obtain clinical benefit as measured by improved movement of a paralyzed limb, the trial is not designed for that purpose. Instead, the phase 3 trial is designed to test efficacy. A phase 3 trial is usually a randomized, placebo-controlled trial using the optimal dose and timing, based on results from the phase 1–2 trials. There has been one successful phase 3 trial of stem cells in seventy patients with SCI,¹³ so this treatment is still many years away from clinical use. There are clinics, however, that offer (for large fees, frequently), unproven stem cell therapies. None of these clinics are using stem cells that have proven efficacy or FDA approval. Before you consider such a treatment, you should ask these questions: What are the anticipated benefits and how do you measure them? What’s the mechanism? How are the stem cells made? What are the side effects and risks? Will you provide me with contact information to speak with people you have treated?

What are my options for participating in a stem cell trial, and will I benefit? The best way to find stem cell trials that are located near you and are actively recruiting participants is to visit clinicaltrials.gov. More than twenty-five trials have used injections of stem cells to treat ANI. The vast majority of these trials used bone marrow-derived mesenchymal stem cells (BM-MSCs) which are cells from the patient’s own bone marrow. Their use in cell therapy is primarily to stimulate the intrinsic regenerative properties of injured tissues by releasing growth and differentiation factors, not by making new tissue themselves. Among the MSC trials for SCI, eight out of ten found improvements in strength and sensation that persisted for over one year. The largest trial (seventy patients) included people post-SCI by ten or more months with no recent neurologic improvement.¹⁴ Among the fifty patients who received both rehabilitation therapy and transplantation of autologous BM-MSCs, nearly half had significant improvements in daily function, motor strength, and sensation, with no serious side effects, while the twenty control patients showed no change.

There have been forty-three completed clinical trials of stem cells, predominantly autologous BM-MSCs for the treatment of stroke.¹⁵ The major difference from the SCI trials was that most patients were treated within seven days of their stroke. In the three largest trials completed, there were no significant benefits at three months.¹⁶

There have only been nine trials of stem cells for TBI, and only two of these have been completed.¹⁷ The largest trial randomized forty patients with chronic TBI (>10 months post-injury) to MSCs derived from the umbilical cord compared to the usual treatment. There were statistically significant improvements of motor function in the upper and lower extremities, as well as sensation and balance.¹⁸

In summary, stem cell therapy for ANI remains at the earliest stages of development. Many important questions haven’t yet been answered, including the type and dose of transplanted cells, best route of administration, timing relative to the initial injury, patient selection, biomarkers, effect of medications being taken as part of routine care (both positive and negative), and duration of benefit. The results of these trials are promising, but the degree of success has been limited. The good news is that none of these treatments has caused serious side effects. Unfortunately, though, none of the studies reported efficacy that would meet the standards required by the FDA for approval. You and your doctor should visit clinicaltrials.gov regularly to find trials that you may participate in, as well as the results of ongoing trials.

Drugs to Mobilize and Differentiate Stem Cells

While it’s likely that different types of stem cells will be required to treat different ANIs, a common area of investigation will be the use of drugs to mobilize stem cells that are present in brain tissue. It has been well established that the brain’s memory center (hippocampus), the smell center (olfactory nerve), and the ventricles of the brain contain stem cells. Our understanding of how to use drugs to differentiate these tissue stem cells into specific brain cell types (neurons, astrocytes, and glia) damaged by ANI is rapidly advancing.

Scaffolds and Drugs to Promote Nerve Regeneration

Improving regeneration of nerve tissues will require a multipronged approach. A key component is likely to be a scaffold that creates an environment favorable to regeneration. A more recent approach to regenerating nerves in people with SCI has been to combine stem cell transplantation with engineered scaffolds.¹⁹ Scaffolds are made of proteins and other substances that together are called a “matrix,” which has the consistency of gelatin. Some of the common matrix proteins are collagen, fibronectin, glucosamine, and chondroitin. These proteins assemble to form structures that look like scaffolds on buildings, which provide support and orientation to build and repair tissue. Several different types of scaffolds have been tested for nerve regeneration (most frequently in animals with SCI). These include scaffolds that contain enzymes that degrade scar tissue, release nerve growth factors, and provide shape and structure for the tissue. For treating SCI, these enzymes and growth factors are placed directly at the site of the SCI using nanoparticles or liposomes that release these factors in a slow, controlled manner over days to weeks. Finally, some specialized polymers may be injected to create 3D-scaffolds and tubes that enable the nerves to grow through the scar in the correct direction.

Neuroplasticity: Devices and Drugs

Through the concept of neuroplasticity, you can restore the function of your brain and body, bringing functionally dead parts of your nervous system back to life. Two key requirements for neuroplasticity are learning and practicing.

Computer-assisted learning: We all know that the more we practice a skill, the better we become at it. The same holds true for our senses, such as hearing, smelling, and seeing. If you had a TBI or stroke that caused you to experience vision loss, you would have to learn how to see again. I faced a similar problem learning how to hold a wine glass.

Learning often takes a lot of practice and repetition. But what if this learning process could be accelerated? For relearning vision, you need to know what to look for and how to consciously recognize the image your brain receives (perception). In one study, subjects performed a “motion threshold” task in which they learned how to detect motion of one marked object moving among many objects. They were then asked to perform the task while given different types of brain stimulation, each involving a noninvasive electrical current applied over the visual cortex. The researchers found that one type of brain stimulation, transcranial random noise stimulation (tRNS), had remarkable effects on improving the motion threshold.²⁰

They extended their findings to patients who had suffered a stroke or TBI that made them partially blind. Combining tRNS brain stimulation with visual training therapy resulted in significant improvement in visual perception and function after only ten days.²¹ More impressive, the improvement lasted more than six months, demonstrating permanent neurorestoration. It’s possible that similar techniques can be used to improve other senses such as touch, temperature, taste, smell, and proprioception. Combining novel computer-based sensory training programs with tRNS represents a new approach to neurorestoration of human sensation, which represents an important advance in therapy.

Virtual reality: Virtual reality (VR) has been well studied in promoting the rehabilitation of motor, cognitive, and psychosocial functions in ANI patients, especially those with TBI.²² VR has become cost-effective with improvements in head-mounted displays and hand controllers that can be purchased for $200 to $600. It’s safe, though it may cause mild vertigo. VR offers the ability to simulate environments that foster neuroplasticity. It’s particularly effective for complex functional actions, such as walking with a cane, reaching for and grabbing an object with one hand, or raising or lowering the object with two hands. Motions can be simulated with your hands each holding a controller that moves your avatar, a simulated figure of yourself. Repetitive trials using the avatar can be performed quickly, safely, and with no assistance to achieve the desired result. Because it’s virtual, muscle fatigue is minimal and restarting the therapy takes no time or effort. Furthermore, VR can begin with easy tasks that become increasingly difficult on an individualized basis. This enables you to be successful at your appropriate level, and because success breeds success, the psychological aspects are positive rather than negative—especially important since many ANI patients have reactive depression. In addition, potentially dangerous or anxiety-provoking tasks, such as walking without handrails or a walker, can be performed without fear. To address the requirements of performing the activities of daily living, training multiple motor, sensory, and cognitive skills (“walking and chewing gum at the same time”) is necessary. VR offers unique advantages to address this challenge because its interactive nature encourages training in an individualized manner. A clinical trial of VR in people with stroke and TBI showed that VR training improved performance not only in the trained task but also in specific neuropsychological functions such as visual memory retrieval. A review of studies that tested the effect of VR in people with TBI found that VR had the potential to be an effective assessment and rehabilitation tool for treatment of cognitive and behavioral impairment.²³ As computer and hardware technology improves, the use of VR in rehabilitation will likely be a major tool.

Enhancing Learning and Neuroplasticity

A fundamental concept for neurorestoration is learning how to perform old tasks using new nerves. Therefore, neuroplasticity must begin by understanding the mechanisms by which we learn: how memories are stored and then retrieved to perform learned tasks. This type of neuroplasticity requires that molecules be released from one nerve to the next to enable communication (hence the name, “neurotransmitters”) between the parts of the brain that are responsible.

Molecules and proteins that stimulate neuroplasticity: Although many molecular signaling pathways are involved in learning and neuroplasticity, brain-derived neurotrophic factor (BDNF) has emerged as a prime facilitator of motor learning and rehabilitation after ANI.²⁴ Two strategies that have been shown to increase BDNF levels are aerobic exercise and certain neurotransmitters.²⁵ The therapeutic use of BDNF and these neurotransmitters has been shown in animals and will hopefully be tested in humans soon.²⁶

Drugs: Accelerating learning and enhancing memory with drugs has enormous appeal for treatment of many neurological diseases. Drugs that promote neuroplasticity are called nootropics (from the Greek meaning “mind” and “a turning”), smart pills, or cognitive enhancers. Their benefits are measured by improved cognition, creativity, attention, memory, and decision-making. At this time, there are no FDA approved nootropics. However, there are many candidates²⁷:

• The best cognitive enhancers are stimulants, like caffeine, and the prescription drugs dextroamphetamine and methylphenidate, which are used to treat attention deficit with hyperactivity disorder (ADHD). In particular, the classes of stimulants that demonstrate cognition-enhancing effects activate membrane proteins called receptors, especially the dopamine receptor D1 and adrenoceptor A2.²⁸

• Donepezil is used to treat dementia in patients with Alzheimer’s disease. It has been shown to improve memory, awareness, and the ability to function. It is an enzyme blocker that works by restoring the balance of endogenous neurotransmitters in the brain.²⁹

• Selective serotonin reuptake inhibitors (SSRIs) have also shown promise. The first large-scale randomized clinical trial of SSRIs in acute stroke patients found that initiating the SSRI fluoxetine (Prozac) immediately after a stroke improved motor function at ninety days. This trial randomized half the patients to a placebo and half to fluoxetine, regardless of whether they had depression. Furthermore, an analysis of over four thousand stroke patients from multiple trials (including patients given SSRIs for depression) showed a similar benefit of SSRIs in recovery.³⁰

Improving learning and memory with drugs alone has not been nearly as successful as using devices, but because there is such an enormous amount of research on people with dementia, it’s likely that new drugs useful to people with ANI will also become available.

Integrative Medicine

Acupuncture

Traditional acupuncture involves needle insertion, moxibustion (burning dried mugwort on the skin over acupuncture meridians to improve circulation), and cupping therapy, as well as feeling the pulse for the strength and symmetry of your qi. Although many health providers think that acupuncture’s benefits are due primarily to a placebo effect, recent studies in animals and people have identified a logical mechanism that has implications for new approaches to treating pain. Specifically, it was found that adenosine, a neuromodulator with pain-relieving properties, was released during acupuncture. Injection of a drug that activated the adenosine receptor also caused pain relief. With this knowledge, it should be possible to replicate the benefits of acupuncture using specific drugs, perhaps in combination with acupuncture needles.³¹

Probiotics

The communication between your gut microbiome (the bacteria that live in your intestines) and brain affects many aspects of brain function, including immune cell activation, formation of the blood-brain barrier, formation of new neurons, and myelination. Because the gut microbiome can be modified easily using antibiotics or probiotics, it represents a new target for drug development and for probiotic modulation. Several studies have shown effects of probiotics to alter the inflammatory response mediated by microglia and infiltrating macrophages, thereby protecting neurons from death. Future studies that identify beneficial molecules made by certain types of bacteria should provide new avenues for ANI therapies based on probiotics.³²

Traditional Chinese Medicine (TCM)

TCM medications are currently not well understood in Western medicine. The variation among different manufacturers is so great that they are not safe to use. The Chinese government is spending more than $200 million each year to identify the molecules present in the medicines. I anticipate that new drugs will emerge from this intense research, some of which should be beneficial for people with ANI.

How to Participate in Clinical Trials

Progress in neurorestoration can only occur if clinical trials take place. There are many promising therapies on the horizon, so there should be opportunities for you to participate in a trial, if you so choose. There are three good reasons to volunteer for a clinical trial. First, you will be contributing to development of a possible new therapy for people like you. Second, you will receive high-quality clinical care that may improve your health in areas other than the objective of the trial. This care comes free of cost, and some trials may pay you for your participation. Third, you may benefit from a drug that you would not otherwise receive until FDA approval, which can take several years.

But there are a few caveats. It’s possible that there may be unintended harmful side effects of the treatment. And participation in certain trials, especially those that require an intervention, may exclude you from future clinical trials. This is particularly likely if you receive stem cells or have a device implanted over your spinal cord or brain.

How to Find the Right Clinical Trial

Only participate in trials that have stringent safeguards. The trial’s protocol should have undergone strict review by an Institutional Review Board (IRB), a standing committee of physicians, statisticians, community advocates, ethicists, and other experts who assess the risks and benefits to make the trial ethical and as safe as possible. They ensure that the participants are well informed and that their rights are protected. When you enroll, you should receive “informed consent” that describes the trial in as much detail as possible, especially the risks. You should never have to pay for a legitimate trial. Be extremely cautious about enrolling in a trial outside the United States, because not all countries have the same stringent reviews for safety.

You should believe in the potential benefit and significance of the therapy: There’s nothing wrong with choosing a trial that may benefit you personally. But it’s important to understand that the best trial designs include a placebo group. Neither you nor the investigators know who gets the therapy and who gets the placebo.

Your own doctors and family should support your decision: You should trust completely in the investigators who are leading the trial, and you should have the full support of your doctor and your family.

A Bright Future

Some of the devices, drugs, and other therapies discussed here may seem far-fetched. Certainly, a few years ago, some of them would have sounded like science fiction. But all of these things are real and hold great promise for neurorestoration after ANI. I have no doubt that some of the disabilities people live with after stroke, SCI, and TBI will be readily and effectively addressed with the therapies we see on the horizon. If you had told me about the iPad the month before my injury, I would have assumed that my ability to purchase one would be several years away. Yet it showed up only ten months after my injury. And as I look into the future, I’m confident that the inventiveness of the human mind and our unquenchable thirst to discover and create will bring many new treatments that make our lives even better.